Method for evaluating and treating hypertension

ABSTRACT

The Laragh Method is a novel method useful for evaluating and treating hypertensive patients. The Laragh Method provides a systematic approach for the physician to use volume vasoconstriction information with entry and induced changes in blood pressure and in ambulatory plasma renin levels for the rational selection of treatment tailored to suit each individual hypertensive patient. The Laragh Method provides a systematic and rational approach to drug selection which greatly improves the therapeutic success rate among hypertensive patients and which for the large majority provides long-term blood pressure control with one drug instead of two or two instead of three with each drug rationally targeted to control the renin and/or volume elements in the blood pressure equation.

FIELD OF THE INVENTION

The present invention relates to new and useful methods for theevaluation and treatment of hypertension.

BACKGROUND INFORMATION

Hypertension is a sustained elevation of blood pressure that can lead toheart attack, heart or kidney failure, stroke, and other cardiovasculardiseases. Hypertension affects about 20% of the population worldwide. Amajor problem is that the current methods that are widely used for thedetection and treatment of hypertension are inadequate and result inenormous personal suffering and economic costs.

The Economic Costs of Hypertension

The 1999 Annual Report of the American Heart Association estimates thedirect cost of hypertension in the United States to be $26.1 billionannually, plus an additional $11.1 billion in indirect costs arisingfrom lost productivity due to morbidity and mortality (Table 1).Moreover, the link between hypertension and other cardiovasculardiseases has become increasingly evident. TABLE 1 Economic Costs ofHypertension in the US ($Billion) Coronary Congestive Total Heart ArteryHeart Cardiovascular Disease Disease Stroke Hypertension Failure DiseaseDirect Costs Hospital/Nursing $78.9 $42.0 $25.0 $7.4 $15.5 $128.4 HomePhysicians/Other 14.4 8.1 2.3 8.1 1.5 28.2 Professionals Drugs 7.3 3.50.4 9.0 1.1 17.7 Home Health/Other 5.2 1.6 2.9 1.6 2.2 11.5 MedicalDurables Total $105.9 $55.2 $30.6 $26.1 $20.3 $185.8 Indirect Costs Lost17.2 7.2 5.6 5.2 NA 27.6 Productivity/Morbidity Lost 91.6 55.8 15.1 5.92.2 113.2 Productivity/Mortality Grand Total $214.7 $118.2 $51.3 $37.2$22.5 $326.6Source: American Heart Association 1999 Annual ReportNumber Affected and the Low Rate of Treatment Success

It is estimated that in the United States alone there are about 50million hypertensives, of whom only about 68% have had theirhypertension diagnosed (Table 2). Among the estimated 34.2 millionidentified hypertensives receiving medical treatment, only 27% havetheir blood pressure adequately controlled. A more conservative estimatesuggests that this rate may be as low as 12%, and in other countries,the treatment success rates may be even lower: 12% in France, and 9% inBritain. Moreover, the available data indicate that the success rate oftreatment has actually fallen during the past several years, despite theavailability of new and powerful antihypertensive medications.

Poor success rates in the management of hypertensive patients haveresulted from empirical approaches to selecting antihypertensive drugs.This empirical approach is recommended by authorities, and followed bymany physicians. For example, in the United States, the Joint NationalCommittee (JNC) on Prevention, Detection, Evaluation, and Treatment ofHigh Blood Pressure periodically surveys the literature and currentknowledge on hypertension. The current recommendation of the JNC (JNCVI) is to use a diuretic or a β-blocker—among the oldest classes ofantihypertensive drugs—as a first line treatment.

The recommendations of the JNC VI are based on a traditionalepidemiological model in their evaluation of hypertension treatment. Inthis model, hypertension is assumed to be a single process disease inwhich all patients have a common pathophysiological mechanism. Whenblood pressure does not decrease in response to empirical treatmentswith either diuretics or β-blockers or both, several different drugtypes are added until blood pressure is subdued. This empirical approachto treatment is referred to as “stepped care”. Stepped care results inmany patients being treated with at least two different antihypertensivedrug types. This approach tends to increase the long term expense oftreatment and to promote more adverse side effects. Perhapsconsequently, only a small proportion of patients complies with theirantihypertensive drug regimen, which further reduces the possibility ofachieving blood pressure control. For example, a recent study inCalifornia showed that only 6% of the hypertensive Medicaid populationadhere to their drug treatment regimens. TABLE 2 Detection and Treatmentof Hypertension in the US 1988-1991 1991-1994 Awareness 73% 68%Treatment 55% 54% Control 29% 27%Source: Joint National Committee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure (JNC VI)

Therefore, a great need exists for methods to successfully evaluate andtreat hypertensive patients in order to reduce both the enormous costassociated with hypertension, and consequential costs of cardiovasculardiseases, which is estimated at about 15% of the $1.2 trillion annual USHealth Care bill.

SUMMARY OF THE INVENTION

The present invention discussed herein provides novel methods orsystems—the Laragh Method—for evaluating and treating hypertensivepatients. The Laragh Method provides a systematic approach that allowsphysicians and other health care providers to select the appropriatetreatment, tailored to suit each individual hypertensive patient. TheLaragh Method greatly improves the therapeutic success rate amonghypertensive patients and uses more rational drug selection as comparedto the traditional, empirical “stepped care” approach.

The stepped care approach is conceptually flawed because it fails torecognize the heterogeneity of biochemical mechanisms involved amongdifferent hypertensive patients. The Laragh Method incorporates theconcept that high blood pressure, like fever, is a physical sign thathas several identifiable causes and underlying abnormal mechanisms. Justas fever cannot be appropriately treated with a single recipe, neithershould hypertension.

Unlike the recommendations of the JNC, which are based partly on thepreconception of a single process and other epidemiologicalconsiderations, the Laragh Method evaluates and treats the identifiablepathogenic mechanisms that caused blood pressure to rise in theindividual patient in the first place.

The Laragh Method can be used to evaluate and treat previously untreatedhypertensive patients as well as patients who have undergone or arereceiving unsuccessful treatments. In addition, the Laragh Method may beused to evaluate and treat hypertensive crises.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the renin-angiotensin-aldosterone system.

FIG. 2 illustrates the typical effects of anti-volume drug types, asdefined by the Laragh Method, on blood pressure and on plasma reninactivity in previously untreated hypertensive patients.

FIG. 3 illustrates the typical effects of the anti-renin drug typesdefined by the Laragh Method on blood pressure and on plasma reninactivity in previously untreated hypertensive patients.

FIG. 4 is a flow chart depicting an exemplary embodiment of the LaraghMethod for the evaluation and treatment of previously untreatedhypertensive patients.

FIG. 5 is a flow chart depicting an alternate exemplary embodiment ofthe Laragh Method used for the evaluation and treatment ofunsuccessfully treated hypertensive patients.

FIG. 6 illustrates suggested changes in therapy called for by the LaraghMethod in unsuccessfully treated patients on anti-volume drugs based ontheir treatment plasma renin levels.

FIG. 7 illustrates suggested changes in therapy called for by the LaraghMethod in unsuccessfully treated patients on anti-renin drugs based ontreatment plasma renin levels.

FIG. 8 illustrates the use of plasma renin levels to select drugtreatments to reduce the cardiovascular risks associated with excessplasma angiotensin levels.

DETAILED DESCRIPTION

FIG. 1 is a schematic illustration of the renin-angiotensin-aldosteronesystem. The normal function of this system is generally believed toraise blood pressure when it is too low and thus maintain blood pressureduring upright posture and exercise or during periods of dehydration orsalt loss. However, excessive kidney renin secretion, leading to higherplasma renin levels, is associated with hypertension, heart attack,stroke, and other cardiovascular disease.

Mechanisms of Blood Pressure Control and Antihypertensive Drugs

Blood pressure is determined to a large extent by a combination of twofactors: the size of the blood volume and the degree of constriction ofarterioles, small muscular blood vessels at the periphery of thevasculature. Blood volume is determined largely by the amount of sodiumin the body, which osmotically retains fluid in the body and therebyenlarges the blood volume. The constriction of arterioles is controlledby several factors, the most important of which is the amount of renincirculating in the blood. Renin is a hormone released by the kidney intocirculation. Renin's only known action is to enzymatically releaseangiotensin I, a decapeptide, from circulating angiotensinogen.Angiotensin I has no pressor action but it is rapidly “converted” to anoctapeptide, angiotensin II, by converting enzymes lining blood vesselwalls and circulating in the bloodstream. Angiotensin II causes theblood vessels to constrict. Thus, blood pressure is elevated when theplasma levels of renin-angiotensin or the body sodium content areexcessive.

The release of renin into the blood is the first step in a rapidsequence of events that raises blood pressure:

-   -   In normotensive individuals, renin secretion is stimulated        either by a fall in blood pressure or low blood volume, the        latter usually caused by salt depletion. Conversely, the renin        system is normally turned off by higher blood pressures or salt        intake.    -   Renin acts on a plasma protein (angiotensinogen) to release        angiotensin I, which is then converted by angiotensin converting        enzyme (ACE) in blood vessel walls into angiotensin II.    -   Angiotensin II instantly constricts the blood vessels, thus        maintaining or elevating blood pressure.    -   Angiotensin II also stimulates the adrenal glands to produce        aldosterone, that causes salt retention that raises blood volume        and flow to restore blood pressure.    -   When blood pressure and blood volume have been restored, kidney        renin secretion is turned off by the improved blood flow to the        kidneys.    -   In normotensives, there is always a reciprocal relationship        between salt intake and plasma renin. As salt intake and blood        pressure rise, plasma renin activity falls. Conversely, when        salt intake falls, plasma renin levels rise. However, in        hypertensives, plasma renin levels may be elevated despite        normal salt intake and despite elevated blood pressure. Because        elevated blood pressure should turn off renin secretion, any        amount of plasma renin in a hypertensive individual is abnormal.        Only in low-renin hypertensive patients does renin release        behave normally, and in them, blocking renin activity will have        no effect on blood pressure. In hypertensive patients with        “normal” or high plasma renin levels, the kidney renin behaves        abnormally because in normal people a high salt intake or a        higher blood pressure will promptly “turn off” kidney renin        release and plasma renin will fall to zero. This is proved by        the fact that blocking plasma renin in normal and high renin        hypertensives will promptly correct their hypertension.

The Laragh Method approach to the management of hypertensive patientsrecognizes that hypertension can result from a spectrum of conditionsranging from those that are largely volume-dependent (sodium mediated)to those that are largely vasoconstriction-dependent (reninangiotensin-mediated). The available antihypertensive drugs all act tocurtail either the sodium factor or the renin factor. Knowing the plasmarenin or angiotension level, the Laragh Method can be used to select theright drug type to treat the specific mechanisms that underlie thehypertension in each individual patient.

The Laragh Method provides a framework for exposing and understandingthe failures of widely used antihypertensive strategies. For example,when the vasoconstriction (i.e., renin) arm of the blood pressurecontrol system is blocked by antihypertensive medication, reactiveincreases in the activity of the renin system can occur that blunt theefficacy of the drug. Compensatory changes can also occur so thatblocking one mechanism will cause an increase in the activity of theother component (i.e., vasoconstriction or volume) such that bloodpressure remains elevated. Together, these two offsetting reactions canfurther reduce the effectiveness of an antihypertensive drug program.

Because empirical approaches to antihypertensive therapy are populationbased and fail to select drugs for the individual patient based on themechanism of their disease, a patient could receive a drug for lifewhich is ineffective in controlling his or her blood pressure. Further,even if the right drug is fortuitously prescribed, the reactive andcompensatory changes that occur during treatment may overcome, ormitigate the effects of the drug. This leads to further unguidedexcessive manipulations of antihypertensive medication programs.

Two Basic Types of Hypertensive Patients

The pharmacologic treatment of the hypertensive patient is a complexdecision-making process. It is complicated by the fact that there aremany pharmacologically distinct drug classes available and thathypertensive patients are not all alike mechanistically so thatindividual hypertensive patients respond quite differently to thevarious different types of anti-hypertensive drugs,. Diuretics, specificaldosterone receptor blockers, calcium channel blockers, alpha blockers,beta blockers, ACE inhibitors, angiotensin receptor blockers andcentrally acting alpha agonists, comprise the major categories. Theproblem of which drug to chose for a particular patient is furthercomplicated by the availability of many different products within theseclasses, which are often claimed by their maker to differ importantlyfrom other products in the same class. Such marketing claims furtherconfuse physicians and patients

The Laragh Method overcomes these problems by classifying hypertensivepatients into two major categories based on PRA levels: (1) those withPRA levels <0.65 ng/ml/hr who have predominantly sodium-volume mediatehypertension, and (2) those with PRA levels >0.65 ng/ml/hr who havepredominantly and progressively more plasma renin-angiotensin mediatedvasoconstrictor hypertension. TABLE 3 TWO BASIC TYPES OF HYPERTENSIVEPATIENTS PRA levels < 0.65 ng/ml/hr: Have predominately sodium-volumemediated hypertension PRA levels ≧ 0.65 ng/ml/hr: Have predominatelyplasma renin- angiotensin mediated vasoconstrictor hypertensionTwo Types of Drugs

The Laragh Method simplifies the approach to treatment by classifyingthe available anti-hypertensive drug classes according to their majormode of action into two major categories:

-   -   Drugs that lower blood pressure by reducing or blocking the        activity of the renin-angiotensin system.

Drugs that reduce blood pressure because of primary or secondary actionsto reduce body sodium and volume content by enhancing renal sodiumexcretion. TABLE 4 TWO BASIC TYPES OF ANTIHYPERTENSIVE DRUGSAnti-Na⁺-Volume “V” Drugs Primary Thiazide and Loop Diuretics SARA,*e.g., Spironolactone Secondary α-Blockers Ca²⁺ Antagonists (CCB)Anti-Renin-Angiotensin “R” Drugs ACE Inhibitors (block A_(II) Formation)Ang II Receptor Blockers (ARB) (block A_(II) action) β-Blockers (reducekidney renin secretion)*Specific Aldosterone Receptor Antagonists

The drugs listed below and the accompanying dosage ranges are exemplaryand are not intended to limit the drugs or dosages which may be used inthe Laragh Method.

Anti-Sodium Volume “V” Drugs

Included in this category are the drugs that have a primary natriureticaction on the kidneys, i.e., they reduce body sodium and water content.In general, diuretics work by preventing reabsorption of salt and waterfrom renal tubular urine by the kidneys. Thus, the sodium and watercontent in the body decreases leading to falls in cardiac output (theamount of blood the heart pumps) and later followed by a reduction intotal peripheral resistance (the degree to which blood vessels areconstricted and, thus, resist blood flow). Both changes contribute tosalt depletion and drop in blood pressure. Drugs in this class includethe thiazide or loop diuretics, and the specific aldosterone receptorantagonists (SARA), which have potent natriuretic-diuretic actionwithout K⁺ loss, while also blocking other effects of the hormonealdosterone mediated by its receptors. A second class ofnatriuretic-diuretic drugs involves agents which may have anotherprimary anti-hypertensive action but which also act on the kidneys topromote natriuresis. Thus, the calcium channel blockers (CCB) lowerblood pressure by reducing intracellular calcium levels in the smallblood vessel walls, but also have a natriuretic effect because of theirrenal vasodilatation. The alpha blockers reduce alpha adrenergicvasoconstrictor effects and promote natriuresis. These drugs block alphareceptors in the arteries and prevent norepinephrine from reachingreceptors in the heart and kidneys which results in vasodilatation and aconcomitant reduction in blood pressure. These CCBs and alpha blockersare not classical anti-sodium volume drugs, but they are included in theanti-volume drug group because their natriuretic effects have been shownto facilitate their anti-hypertension action and to make them especiallyeffective in low renin-high volume hypertensive patients. Other drugsthat may be discovered or developed in the future may also be used as Vdrugs if they have similar mechanisms of action or act similarly toother V drugs in the Laragh Method.

Diuretics

Available diuretics include, but are not limited to, thiazides, loopdiuretics, SARA drugs, and combination drugs. Thiazides include, but arenot limited to, the following: bendroflumethiazide (Naturetin) 2.5 to5.0 milligrams per day; chlorothiazide (Diuril) 125 to 500 milligramsper day; chlorthalidone (Hygroton, Thalitone) 12.5 to 50 milligrams perday; hydrochlorothiazide (Esidrix, HydroDIURIL, Oretic) 12.5 to 50milligrams per day; indapamide (Lozol) 2.5 to 5.0 milligrams per day;methylclothiazide (Enduron) 2.5 to 5.0 milligrams per day; andmetolazone (Zaroxolyn, Mykrox) 0.5 to 5.0 milligrams per day.

Loop diuretics include, but are not limited to, bumetanide (Bumex) 0.5to 5.0 milligrams per day; ethacrynic acid (Edecrin) 25 to 100milligrams per day; and furosemide (Lasix) 20 to 320 milligrams per day.

Specific aldosterone receptor antagonists (SARA's) reduce sodium andwater content of the body but prevent excessive loss of potassium inurine. These SARA drugs include, spironolactone (Aldactone) 12.5milligrams per day.

Combination drugs are available which comprise traditional diureticstogether with a SARA drug. They include Spironolactone withHydrochlorothiazide (Aldactazide) 50 to 100 milligrams per day.

Secondary V Drugs

The so-called secondary V drugs include calcium channel blockers andalpha blockers. Traditional calcium channel blockers include, but arenot limited to, the following: amlodipine (Norvasc) 2.5 to 10.0milligrams per day; diltiazem (Cardizem) 90 to 360 milligrams per day;diltiazem-sustained release (Cardizem SR) 120 to 360 milligrams per day;Diltiazem-extended release (Dilacor XR) 180 to 360 milligrams per day;Felodipine-sustained release (Plendil Extended Release) 5 to 10milligrams per day; Isradipine (DynaCirc) 2.5 to 10.0 milligrams perday; Nicardipine-sustained release (Cardene SR) 60 to 120 milligrams perday; Nifedipine (Adalat, Procardia) 30 to 120 milligrams per day;Nifedipine-sustained release (Adalat CC, Procardia XL) 30 to 90milligrams per day; Verapamil (Calan, Isoptin) 80 to 360 milligrams perday; and Verapamil-long acting (Calan SR, Isoptin SR, Verelan) 120 to360 milligrams per day.

Secondary V drugs also include newer calcium channel blockers including,but not limited to, Diltiazem-sustained release (Tiazac); Nisoldipine(Sular); Verapamil-extended release (Covera-HS); Lacidipine (succeededin early drug trials and may be available soon); and Manidipine(available in Europe).

Secondary V drugs also include alpha blockers. Available alpha blockersinclude, but are not limited to, the following: doxazosin (Cardura) 1 to16 milligrams per day; labetalol (Normodyne, Trandate) 200-1,200milligrams per day; prazosin (Minipress) 1 to 20 milligrams per day; andterazosin (Hytrin) 1 to 20 milligrams per day.

The Effect of V Drugs on PRA Levels

It is important to understand that there is a reciprocal relationshipbetween PRA and blood pressure. High blood pressure suppresses reninsecretion whereas low blood pressure increases renin secretion. PRAlevels should fall when hypertension initially develops in hypertensivepatients. This effect of high blood pressure to lower renin explains whymany hypertensive patient do in fact have subnormal blood renin levels.Reciprocally, effective therapy to lower blood pressure usually causesthe PRA to rise because the falling blood pressure stimulates reninsecretion. This means that if the PRA level in a patient does notincrease during treatment (with any antihypertensive drug other than abeta blocker, or centrally acting adrenergic drugs that act by loweringrenin secretion), the drug is either not effective, or the dose is toosmall, or the patient is not taking the drug. Over and above thestimulatory effects on renin of a fall in blood pressure, thenatriuresis induced by diuretics or by the specific aldosterone receptorantagonists also increases PRA levels by turning turn off a signal fromthe macula densa region of the nephron. This dual action means that whendiuretics or SARAs lower blood pressure, PRA levels are likely toincrease to a greater extent than they do when hypertension is correctedby the other anti-volume drugs, the calcium channel blockers (CCBs) oralpha blockers.

FIG. 2 shows the expected changes in BP and plasma renin levels inducedby anti-volume drugs in hypertensive patients in relation to theirbaseline PRA levels. Note that the PRA levels are shown on a logarithmicscale. The left-hand-side of the arrows indicate the BP and PRA levelsof untreated patients. The head of the arrows indicate the BP and PRAlevels of the same patients during treatment.

As indicated in FIG. 2 anti-volume drugs are most effective in patientswith PRA <0.65 ng/ml/hr. Such patients usually have only a smallreactive rise in PRA levels. The Laragh Method incorporates theseobservations.

Patients with PRA levels equal to or greater than 0.65 ng/ml/hr arelikely to have a lesser fall in BP as they may have both volume andvasoconstrictor components to their blood pressure.

As PRA levels rise, patients are less and less likely to respond toanti-volume drugs since they are likely to have less and less of avolume component and more of a renin component to their BP. Moreover,the higher the baseline PRA the more likely that V drugs will induce alarge reactive rise in PRA levels. Because the higher PRA level is morevasculotoxic, these patients are unlikely to gain any cardio-protection,even if the diuretic induces a small fall in blood pressure.

Renovascular hypertension should always be considered as a possiblediagnosis in any patient with baseline PRA levels >1.5 ng/ml/hr. In somerenovascular hypertensive patients blood pressure may actually risefurther during diuretic therapy because of their very large reactiverises in renin secretion and thus plasma renin levels.

Anti-Renin “R” Drugs

Anti-renin “R” drugs either (1) reduce the kidney secretion of renin(beta blockers), (2) prevent angiotensin II from being formed by renin(angiotensin converting enzyme inhibitors), or (3) prevent angiotensinII from engaging its receptor in the blood vessel wall (angiotensinreceptor blockers). Thus, all three act at different points to impairrenin system function. All three, however, are less than completeblockers of the renin-angiotensin system. Therefore, and because theyblock the renin system at different points, all three can be used incombinations with each other to more completely block the renin systemin resistant patients. Other drugs that may be discovered or developedin the future may also be used as R drugs if they have similarmechanisms of action or act similarly to other R drugs in the LaraghMethod.

Available beta-blockers which can be incorporated into the Laragh Methodinclude, but are not limited to, the following: acebutolol (Sectral) 200to 1,200 milligrams per day; atenolol (Tenormin) 25 to 100 milligramsper day; betaxolol (Kerlone) 5 to 40 milligrams per day; Carteolol(Catrol) 2.5 to 10.0 milligrams per day; Metoprolol (Lopressor) 50 to200 milligrams per day; Metoprolol-extended release (Toprol-XL) 50 to200 milligrams per day; Nadolol (Corgard) 20 to 240 milligrams per day;Penbutolol (Levatol) 20 to 80 milligrams per day; Pindolol (Visken) 10to 60 milligrams per day; Propranolol (Inderal) 5 to 240 milligrams perday; Propranolol-long acting (Inderal LA) 60 to 240 milligrams per day;and Timolol (Blocadren) 20 to 40 milligrams per day.

Several newer beta blockers are available and include, but are notlimited to, the following: carvedilol (Coreg); Nebivolol; celiprolol.

In addition to the beta blockers, other R drugs, such as angiotensinconverting enzyme inhibitors (ACE inhibitors) may be used in the LaraghMethod. ACE is an enzyme that catalyzes the conversion of an inactivesubstance, angiotensin I into angiotensin II, a powerfulvasoconstrictor. ACE inhibitors inactivate this enzyme and reduce theamount of angiotensin II in the blood, thereby resulting invasodilatation and lower blood pressure. Among the available ACEinhibitors are the following: benazepril (Lotensin) 10 to 40 milligramsper day; Captopril (Capoten) 12.5 to 150 milligrams per day; enalapril(Vasotec) 2.5 to 40 milligrams per day; Fosinopril (Monopril) 10 to 40milligrams per day; Lisinopril (Prinivil, Zestril) 5 to 40 milligramsper day; Quinapril (Accupril) 5 to 80 milligrams per day; Ramipril(Altace) 1.25 to 20 milligrams per day; Trandolapril (Mavik) 1 to 4milligrams per day; and Moexipril Hydrochloride (Univasc) 7.5 to 60milligrams per day.

Another class of R drugs are the angiotensin receptor blockers (ARB).These drugs block the ability of angiotensin II to constrict thearteries. Angiotensin receptor blockers include, but are not limited to,Irbesartan (Avapro) 150 to 300 milligrams per day; Losartan (Cozaar) 50to 200 milligrams per day; and Valsartan (Diovan) 80 to 320 milligramsper day.

The Effect of R Drugs on PRA

Over and above the stimulatory effects on kidney renin release of aninduced fall in blood pressure, ACE inhibitors (CEI), and angiotensinreceptor blockers (ARB) also directly increase PRA levels. The CEIs andARBs increase PRA because, by preventing either the formation ofangiotensin II or its actions, they cripple the naturally operatingfeed-back suppression of increased plasma angiotensin II levels on renalrenin secretion. That means that when either CEIs or ARBs lower bloodpressure, PRA levels increase much more than when hypertension iscorrected with calcium channel blockers or alpha blockers.

As indicated, beta blockers and centrally acting suppressors of thesympathetic nervous system such as clonidine are the special case. Thesetwo groups are the only class of antihypertensive drugs that lower PRAlevels. They both do so either by blocking or reducing the betasympathetic stimulation of kidney renin secretion. In this way they areremarkably effective for lowering plasma renin and angiotensin IIlevels. It is important to know, however, that, because they onlysuppress renin secretion via the beta receptor, renin levels may not becompletely suppressed PRA levels. If the excessive secretion of renin ina particular hypertensive patient is mediated by another mechanism(e.g., kidney disease), beta blockers will still lower PRA levels, butmay not reduce them enough to optimally lower blood pressure. However,because beta blockers powerfully lower renin secretion they are alsoextremely useful in combination with the other anti-renin drugs becausethey blunt the reactive rise in renin which otherwise can overcome therenin system blockade induced by CEI or ARB treatment. Thus, byreactively secreting more and more renin, a patient can sometimesovercome the blockade of angiotension II formation (CEI) or action (ARB)and the blood pressure goes back up.

FIG. 3 shows the expected changes in BP and plasma renin levels inducedby anti-renin drugs (i.e., “R drugs”) in hypertensive patients inrelation to their baseline PRA levels. Note that the PRA levels areshown on a logarithmic scale.

Patients with PRA levels less than 0.65 ng/ml/hr are unlikely to have afall in BP with anti-renin system drugs because plasma renin levels aretoo low to support the blood pressure. Accordingly too, their PRA levelsare unlikely to increase much on anti-renin drug therapy.

Between PRA levels of 0.65 and 6.5 ng/ml/hr, the higher the baseline PRAlevel the more likely that blood pressure will fall and the greater thelikely fall in BP with anti-renin system treatment.

Above a PRA level of about 6.5 ng/ml/hr (10 times the level at whichcirculating PRA levels begin to affect blood pressure) the bloodpressure response to monotherapy with anti-renin drugs such as CEIs andARBs may become less because when they lower pressure they always inducea reactive rise in renin. Since most anti-renin system drugs block onlyabout 90% of the circulating renin-angiotensin system, a 10 fold rise inPRA levels can completely overcome anti-renin system blockade. Sincerenin secretion is likely to be most reactive in patients with very highbaseline renin levels, the blood pressure of a few patients withexceptionally high plasma renin levels, who are at greatest need foranti-renin system therapy, may not respond adequately to a single Rdrug. However, their PRA level will indicate a dramatic response. Theyneed two or more anti-renin system drugs.

In this regard, beta blockers, because they also curtail a reactive risein PRA, are often useful adjuncts to ACE inhibitors and angiotensinreceptor blockers. ACE and ARBs are also good in combination since theyeach attack the renin system at different locations.

The lack of any PRA rise in a patient taking an ACE or ARB is animportant piece of information. It tells you that the drug is notworking. The reason is either non-compliance or lack of sufficient drug(dose too low) or too low a baseline renin level.

Renovascular hypertension should always be considered in any patientwith baseline or treatment PRA levels of 1.5 ng/ml/hr, or with a largereactive rise in PRA after CEI or ARB treatment.

Combination Therapy

For those patients who have both a renin and a sodium factor, eitherprimary, or reactive to the first drug, combination therapy using one ormore anti-renin and/or anti-volume drugs may prove necessary. For suchpatients, two-drug combinations are possible and might prove effectiveand suitable. Alternatively, combination therapy may be used consistingof only two single drugs which involve both V and R pharmacologicalagents (V/R drugs). Thus, the Laragh Method described herein mayaccommodate the rational application of a single V/R combined drug.

The demonstration of the efficacy of any combination should bedemonstrated in each patient by renin and blood pressure testing. Oncethe combination regimen has been verified using single drugs, one of themany combination pills commercially available may be used forconvenience to reduce the number of tablets required.

Thus, various combinations of beta-blocker and diuretics, for example,may be used as a single drug combination treatment regimen. Such drugsinclude, for example, the following: Atenolol (Tenormin) withChlorthalidone; Nadolol 40-80 milligrams per day withBendroflumethiazide 5-10 milligrams per day (Corzide); and PropranololHydrochloride with Hydrochlorothiazide (Inderide).

Another combination treatment is, for example, a drug which combines anACE inhibitor and a diuretic. Such currently available drugs include,but are not limited to: Captopril with Hydrochlorothiazide (Capozide),individualized dosing; Enalapril 5 milligrams per day withHydrochlorothiazide 12.5 milligrams per day (Vaseretic); Lisinopril10-80 milligrams per day with Hydrochlorothiazide 6.25-50 milligrams perday (Zestoretic); and Moexipril Hydrochloride <30 milligrams per daywith Hydrochlorothiazide 50 milligrams per day (Uniretic).

Yet another combination treatment comprises the combination of an ACEinhibitor and a calcium channel blocker. Such drugs include, but are notlimited to: Amlodipine >2.5 milligrams per day with BenazeprilHydrochloride 10 milligrams per day (Lotrel); Enalapril with Felodipine(Lexxel); and Trandolapril 1-4 milligrams per day with Verapamilhydrochloride 180-240 milligrams per day (Tarka).

Also available are formulations which combine an angiotensin blocker anda diuretic. Such drugs include, for example, Losartan potassium 50-100milligrams per day with Hydrochlorothiazide 1.25-25 milligrams per day(Hyzaar).

Other Classes of Drugs

Other classes of drugs such as central alpha agonists, for example, maybe incorporated into the Laragh Method. Available alpha agonistsinclude: Methyldopa (Aldomet) 500-2,000 milligrams per day; Clonidine(Catapres) 0.2 to 0.4 milligrams per day; Ser-Ap-Es; Guanfacinehydrochloride (Tenex) 1 to 2 milligrams per day; and Guanabenz acetate(Wytensin) 4 to 8 milligrams per day. Because of unpleasant sideeffects, these drugs are rarely recommended.

In addition, drugs which have not yet been developed but which willexhibit properties of a V drug, an R drug, or a combination V/R drug maybe incorporated into the Laragh Method.

Central Importance of the Plasma Renin Activity Test

The plasma renin activity test (PRA) measures the capacity of the reninin the patients blood to form angiotensin in the bloodstream, which actsdirectly and immediately on the small blood vessels to constrict themand raise blood pressure accordingly. A properly performed enzymekinetic plasma renin assay is therefore crucial and central forassessment of plasma renin-angiotensin involvement in hypertension andother related cardiovascular disorders.

The test may be performed by collecting 7 ml or less of venous blood inan EDTA Vacutainer® from a quietly seated ambulatory patient. Fasting orspecial diets are not required. The blood is collected and stored atroom temperature and is not chilled. After separation, the plasma isstored at room temperature until the assay is performed in the next dayor two. For delayed analyses, plasma is frozen and then rapidly thawedfor analysis. The details of the analytical procedure for the enzymekinetic method for measuring renin have been published in J. E. SealeyClinical Chemistry 1991 and by Sealey, James and Laragh 1995 in Laraghand Brenner Second Edition, Hypertension: Pathophysiology, Diagnosis andManagement, Laragh J. H. and Brenner, B. N., (eds.), Raven Press, NewYork, N.Y., pp. 1953-1968, the contents of which are incorporated hereinby reference. The test described therein is hereinafter referred to asthe Sealey, and Laragh PRA test. Tests for measuring PRA which may bedeveloped or adopted in the future and which have substantially equal orgreater sensitivity and accuracy also may be used in the Laragh Method.

There are no special dietary or activity requirements for performing thetest. The patient should not be supine and should have blood drawn inthe normal clinical setting. Knowledge of any use of antihypertensive orcardiovascular drugs is important.

To be properly performed, the PRA test, should achieve maximumsensitivity because this enables a full exploration and definition ofsubnormal plasma renin levels that are encountered in about 30 percentor more hypertensive patients. Maximum sensitivity is achieved by theenzyme kinetic assay which allows the prolonged (18 hour) incubation ofthe plasma sample which generates thousands of copies of angiotensinthat can then be detected by radioimmunoassay.

Thus, by full definition of the subnormal range one may accuratelydiscriminate low renin patients from medium to high renin patients andthereby precisely define who is at risk of premature heart attack andwho is not. The test discriminates those hypertensive patients who havea renin factor (PRA≧0.65 to 10 ng/ml/hr or higher) from those who haveinstead a sodium volume factor in whom the lowness of the PRA values(<0.65) is a direct measure of the sodium volume factor. In short, thoserenin assays which cannot precisely identify low values cannot quantifythe extent of the volume and/or the renin factors in hypertensivepatients. Several simple and direct immunioradiometric methods for reninmeasurements have been published, all of which have a major deficiencyin sensitivity. Another artifact in renin assays is caused by chillingblood and plasma samples which has been shown to cryoactivate proreninto renin (Sealey 1976) leading to artificially high plasma renin valuesof tenfold or more an error which is especially likely to occur indiabetic and in low-renin hypertensive patients.

Using the enzyme kinetic method described above, 30% of untreatedambulatory hypertensive patients (BP>140/95) exhibit low valuesPRA<0.65. Sixty percent have medium values 0.65 to 3.0 and 10% have highvalues >3.0.

Most normal subjects with their lower pressures exhibit somewhat higherrenin values (1.0-3.0 ng/mg/hr) than do hypertensives. This is aconsequence of the raised blood pressure in the renal arteries of thehypertensives acting to suppress their kidney renin release. Because ofthis effect, any plasma renin in the blood should be considered to beabnormal in a hypertensive person, because whenever blood pressure israised in a normal person by salt feeding or by neosynephrine injection,plasma renin values will promptly fall to zero.

We have found that patients with curable renovascular hypertensionconsistently exhibit PRA>1.5 ng/ml/hr and patients with curableadenomatous primary aldesteronism consistently exhibit very low values,i.e., PRA<0.65 ng/ml/hr.

Initiating Treatment Using the Laragh Method

The two general classes of antihypertensive drugs utilized by the LaraghMethod, the anti-volume V drugs and the anti-renin R drugs have beendiscussed above. With this drug classification in hand, the LaraghMethod also divides all hypertensive patients into two major groupsaccording to their plasma renin level: (1) those who are progressivelymore likely to have a renin-angiotensin pressor and vasculotoxic factor(PRA≧0.65 ng/ml/hr) and (2) low renin patients, i.e., those who do nothave a plasma renin factor (PRA<0.65 ng/ml/hr) and who have instead, apredominant sodium-volume factor sustaining the hypertension.

A preferred use of the PRA test to guide initial drug treatment isillustrated below in Table V. If the PRA is not known, it is advisableto start the patient with an R drug because the great specificity ofthese drugs (especially the ARB's) provides powerful diagnosticinformation implicating plasma renin in causation if the blood pressurecrashes and vice versa. No response to an R drug implicates a sodiumvolume mechanism instead. TABLE 5 Using Plasma Renin Activity (PRA) toGuide Initial Drug Treatment of Untreated Hypertensive Patients PRAKnown PRA Unknown PRA < 0.65 Always Always Start with V Start with an Rdrug drug PRA ≧ 0.65 Start with R drug

Patients with PRA ≧0.65 ng/ml/hr normally may not have exclusivelyrenin-dependent hypertension and may have a volume component to theirhypertension. Likewise, low renin patients may have a small renincomponent to their blood pressure. Just as in normotensive people, thesodium volume factor and the plasma renin levels are always interactingin varying proportions to support the observed blood pressure. Thus, thecloser the renin level is to 0.65 ng/ml/hr, the more likely that somedegree of both the renin and sodium-volume components are present.However, because excess plasma renin levels are much more highlyassociated with cardiovascular injury to heart, brain and kidney vesselsthan is excess body sodium-volume, in designing the treatment strategy,the Laragh Method treats the renin factor first and then only if theresponse is poor, does the Laragh Method provide for treatment of thesodium-volume factor instead.

In implementing the Laragh Method, the blood pressure of the patient maybe measured by any one of several methods known to a person of skill inthe art or preferred by an individual physician or health care worker.Target blood pressures, and what constitutes controlled blood pressureor adequately controlled blood pressure, also may be identified by oneof several values or measurements known to a person of skill in the artor preferred by an individual physician or health care worker.Regardless of the actual blood pressure measurement used or the targetor a desired blood pressure selected, the Laragh Method can be used tolower and help control patients' blood pressures.

Certain other tests and procedures mentioned herein (Captopril test,renal vein sampling, renal angiogram, adrenal CT scan, adrenal veinsampling, 24 hr urine aldosterone, hypokalemia evaluation, renalangioplasty, surgical revascularization, unilateral adrenalectomy,etc.), are well known to a person of skill in the art and recognizedtests and procedures and their equivalents may be used. Any actualvalues, measurements or observations obtained by these tests are lessimportant than what the values indicate.

The Laragh Method may indicate that a certain drug should be prescribedand then the patient's blood pressure measured to determine whether thedrug has been effective. This determination of the effectiveness of thedrug by measuring the blood pressure should be done after enough timehas elapsed for the drug to be given an opportunity to act. This timemay vary according to the drug and depend on a number of factors such ashow long the drug takes to be effective. Thus, follow-up visits to anoffice, hospital or clinic and the measurement of blood pressure shouldbe scheduled to take into account the drug being prescribed and how longit takes to act.

In exemplary embodiments of the Laragh Method, drugs which areprescribed may be administered by a physician or health care providerunder the direction of a physician, including, but not limited to, oneor more physician's assistant, nurse, technician, or pharmacist. As usedherein, patients may also administer the drugs to themselves.“Administering” may include, but is not limited to, for example, toprescribe, to provide, to recommend, or to suggest through oral orwritten communication.

Protocol I: Using Plasma Renin Activity (PRA) to Guide Treatment of Newor Untreated Hypertensive Patient

FIG. 4 and Table 6 below outline an exemplary embodiment of the LaraghMethod for the new or untreated patient. In this exemplary embodiment ofthe Laragh Method, the evaluation and treatment comprises a series ofvisits by the patient. In Visit 1 blood pressure (BP) is measured, andblood is drawn to determine plasma renin activity (PRA). In Visit 2, ifthe PRA is less than 0.65, the patient is placed in the volume dependent(V) hypertension category. If the PRA is greater than or equal to 0.65ng/ml/hr, the patient is placed in the vasoconstriction-dependent (R)hypertension category.

A patient in the V category at Visit 2 may start on a low dose V drug.Such a patient in Visit 3 will have his or her BP tested again. If BP iswithin acceptable levels, subsequent visits will involve routinefollow-up. If BP is not controlled, the dose of the V drug is increased.At Visit 4 if BP is controlled, subsequent visits will involve routinefollow-up. If BP is not controlled, an R drug is added to the treatmentregimen. At Visit 5, if BP is controlled, subsequent visits will involveroutine follow-up. If BP is not controlled, the R drug dosage isincreased and blood is drawn to check PRA levels. At Visit 6, if BP iscontrolled, then subsequent visits will involve routine follow-up. If BPis not controlled, the change in the treatment regimen depends on thePRA level. If the PRA level is below 0.65 ng/ml/hr, the R drug isdiscontinued and a second V drug is added. If the PRA level is between0.65 and 6.5 ng/ml/hr, a second R drug is added. If the PRA level isabove 6.5, the V drug is discontinued and a second R drug is added.

As shown in FIG. 4, an alternate treatment protocol for a hypokalemicpatient in the V category is to test for the presence ofsurgically-curable primary aldosteronism at Visit 2, rather thanstarting on a low dose V drug. If the patient is hypokalemic, a 24 hoururine aldosterone test is performed. At Visit 3 if the 24 hour urinealdosterone is normal, the patient should start on a low dose V drug asdescribed above for Visit 2. The steps as described above for Visits 3-6are then followed. If the 24 hour urine aldosterone is high at Visit 3,Visit 4 should comprise an adrenal CT scan and/or an adrenal veinsampling. If the results of the tests conducted in Visit 4 are negative,the patient should start on a low dose V drug as described above forVisit 2. The steps as described above for Visits 3-6 are then followed.If the results of the tests conducted in Visit 4 are not negative, Visit5 may comprise a unilateral adrenalectomy, followed by post-operativefollow-up in Visit 6 and subsequent routine follow-up thereafter.

Conversely, if the patient has been classified as an R categoryhypertensive, at Visit 2 this patient may start on a low dose R drug.This patient in Visit 3 will have his or her BP tested again. If BP iswithin acceptable levels, subsequent visits will involve routinefollow-up. If BP is not controlled, the dose of the R drug is increased.At Visit 4 if BP is controlled, subsequent visits will involve routinefollow-up. If BP is not controlled, a V drug is added to the treatmentregimen. At Visit 5 if BP is controlled, subsequent visits will involveroutine follow-up. If BP is not controlled, the V drug dosage isincreased and blood is drawn to check PRA levels. At Visit 6, if BP iscontrolled, then subsequent visits will involve routine follow-up. If BPis not controlled, the change in the treatment regimen is dependent onthe PRA level. If the PRA level is below 0.65, the R drug isdiscontinued and a second V drug is added. If the PRA level is between0.65 and 6.5, a second R drug is added. If the PRA level is above 6.5,the V drug is discontinued and a second R drug is added.

As shown in FIG. 4, an alternate treatment protocol for a patient in theR category with PRA>1.6 ng/ml/hr is to test for a primary renovascularhypertension as an explanation for the patient's hypertension at Visit2, rather than starting on a low dose R drug. If the PRA level is above1.6, Visit 3 may comprise a captopril test. If the captopril test isnegative, the patient should start on a low dose R drug as describedabove for Visit 2. The steps as described above for Visits 3-6 are thenfollowed. If the captopril test is positive at Visit 3, Visit 4 maycomprise renal vein renin sampling. If the results of the renal veinrenin sampling conducted in Visit 4 are negative, the patient shouldstart on a low dose R drug as described above for Visit 2. The steps asdescribed above for Visits 3-6 are then followed. If the renal veinrenin sampling conducted in Visit 4 is not negative, Visit 5 maycomprise a renal angiogram. If the results of the renal angiogramconducted in Visit 5 are negative, the patient should start on a lowdose R drug as described above for Visit 2. The steps as described abovefor Visits 3-6 are then followed. If the results of the renal angiogramare not negative, Visit 6 may comprise renal angioplasty or surgicalrevascularization, followed by post-operative follow-up and subsequentroutine follow-up thereafter. TABLE 6 EXEMPLARY PROTOCOL FOR NEW ORUNTREATED HYPERTENSIVE PATIENTS BASED ON PLASMA RENIN ACTIVITY (PRA)TESTING Current PRA PRA drug % Patients test result regimen CorrectedDrug changes 1st visit X None  0% None, return 1-3 weeks 2nd visit XNone  0% PRA < 0.65, start V drug PRA ≧ 0.65, start R Drug 3rd visit On25% Increase dose low dose V or R drug 4th visit On 50% Add V to R maxdose or R to V drugs V or R drug 5th visit X On 75% Increase dose of V +R drug 2nd drug 6th visit X On 90% PRA < 0.65, switch max dose R to 2ndV V + R drug drug PRA 0.65 to 6.5, add 2nd R drug PRA ≧ 6.5, switch V to2nd R drug

FIG. 4 and Table 6 above outline an exemplary embodiment of the LaraghMethod for the new or untreated patient by setting forth a schedule ofPRA tests, an analysis of the results of the tests, and the implicationsfor changing drugs based on the results of the tests during a sequenceof office visits. As indicated in FIG. 4 and in Table 6, the untreatedhypertensive patient with a plasma renin (PRA) level at or above 0.65ng/ml/hr is likely to have a renin-angiotensin component to thehypertension that is in proportion to the height of the renin value. Incontrast, patients with suppressed PRA values (<0.65 ng/ml/hr) are morelikely (based on the lowness of the PRA value) to have hypertension thatis caused by excessive sodium-volume retention. In them, the lowness ofthe renin factor indicates the degree of sodium-volume excess. Becauseexcess renin is more vasculotoxic than is excess volume in hypertensivepatients, and because renin-angiotensin is a more common cause ofessential hypertension than sodium-volume, all untreated patients with aPRA level at or above 0.65 ng/ml/hr should be treated initially with adrug that blocks the renin-angiotensin system because if that treatmentis successful, it is more likely to prevent cardiac and vascular damageover the long term. For reasons already discussed, patients with PRAvalues <0.65 ng/ml/hr should be initially treated with a V drug.

Protocol II: Using Plasma Renin Activity (PRA) to Guide Treatment ofUnsuccessfully Treated Patients

As indicated by FIG. 5 and Table 7 below, another exemplary embodimentof the Laragh Method is quite useful for determining which drug or drugsto select for the previously unsuccessfully treated hypertensivepatient. The Laragh Method can be used for (a) patients on one or more Vdrugs, (b) patients on one or more R drugs, or (c) patients receivingone or more R and V drugs. As was the case for Protocol I, an exemplaryembodiment of Protocol II may comprise a series of steps or visits.

Visit 1 (as in Protocol I) may comprise measuring BP and drawing bloodto test PRA levels. The appropriate action to take during Visit 2 isdependent on the PRA level. If the PRA level is below 0.65 ng/ml/hr andthe patient is on a V drug alone, the patient may be treated consistentwith the V side of Protocol I (FIG. 4), Visit 3 or 4. If the PRA levelis below 0.65 ng/ml/hr and the patient is on an R drug alone, the R drugmay be discontinued and treatment with a V drug initiated. This patientin Visit 3 will have his or her BP checked. If BP is controlled,subsequent visits will comprise routine follow-up. If BP is notcontrolled, the patient may be treated consistent with the V side ofProtocol I, Visit 3. If the PRA level is below 0.65 and the patient ison both a V and R drug, the patient should be treated consistent withProtocol 1, Visit 6.

If a patient in Protocol II, Visit 2 has a PRA level between 0.65 and6.5 and is on a V drug alone, such a patient may be treated as if on theV side of Protocol I, Visit 3 or 4. If a patient in Protocol II, Visit 2has a PRA level between 0.65 and 6.5 and is on an R drug alone, such apatient may be treated as if on the R side of Protocol I, Visit 3 or 4.If a patient in Protocol II, Visit 2 has a PRA level between 0.65 and6.5 and is on both a V drug and an R drug, such a patient may be treatedas if in Protocol I, Visit 6.

If the PRA level is above 6.5 and the patient is on a V drug alone, theV drug may be discontinued and treatment with an R drug initiated. Thispatient in Visit 3 will have his or her BP checked. If BP is controlled,subsequent visits will comprise routine follow-up. If BP is notcontrolled, the patient may be treated consistent with the R side ofProtocol I, Visit 3. If the PRA level is above 6.5 and the patient is onan R drug alone, the patient may be treated consistent with the R sideof Protocol I, Visit 3 or 4. If the PRA level is above 6.5 and thepatient is on both a V and R drug, the patient should be treatedconsistent with Protocol 1, Visit 6. TABLE 7 EXEMPLARY PROTOCOL FORUNSUCCESSFULLY TREATED PATIENTS PRA PRA Current Drug changes based ontest result drug regimen treatment PRA Protocol IIa (on one or moreanti-volume drugs) 1st visit X On Return in 1 week Maximum V drug 2ndvisit X On PRA < 0.65, add 2nd V Maximum V drug drug PRA 0.65 to 6.5,add R drug PRA ≧ 6.5, switch to R drug* Protocol IIb (on one or moreanti-renin drugs) 1st visit X On Return in 1 week Maximum R drug 2ndvisit X On PRA < 0.65, switch to V Maximum R drug drug PRA 0.65 to 6.5,add V drug PRA ≧ 6.5, add 2nd R drug* Protocol IIc (on one or moreanti-renin and anti-volume drugs) 1st visit x On Return in 1 week Vdrug + R drug 2nd visit X On PRA < 0.65, switch R to V drug + R drug 2ndV drug PRA 0.65 to 6.5, add 2nd R drug PRA ≧ 6.5, switch V to 2nd Rdrug**The higher the PRA level, the more likely that a 2nd R drug may beneededProtocol IIA: For Unresponsive Hypertensive Patients Already Taking VDrug(s)

In more general terms, as shown in FIG. 5 and Table 7, the Laragh Methodprovides that a patient still in the titration phase of a single V drugshould have the dose of the drug increased to a maximum level as long asthe PRA remains below 0.65 ng/ml/hr. In such a patient the sodium-volumefactor is still operative and contributing to the hypertensive state.Since a renin factor is unlikely to be present in any patient with a lowrenin level, a patient on any V drug who remains hypertensive with a PRAlevel less than 0.65 ng/ml/hr is unlikely to respond to any R drug.Therefore, if a full dose of a V drug has already been tested, andassuming good compliance, a V drug with a different mechanism of actionshould be added. Thus, an exemplary embodiment of the Laragh Methodprovides that a diuretic can be added to a SARA or vice versa, and thenan alpha blocker or CCB, could be added to a diuretic or SARA.

Irrespective of whether the hypertensive patient is untreated or treatedwith a V drug, the higher the PRA level the more likely the patient isto have a renin component to the hypertension. If such an unresponsivepatient is already on a full dose of V drug, the Laragh Method providesthat an R drug should be added if the patient's PRA level is equal to orgreater than 0.65 ng/ml/hr. However, if the patient's PRA is equal to orgreater than 6.5, the Laragh Method directs that diuretics should bestopped and an R drug started because such high renin levels indicatesome dehydration.

Protocol IIB: For Unresponsive Hypertensive Patients Already Taking RDrug (s)

Since a renin factor is unlikely to be present in any treated patientwith a low renin level (except one treated with a beta blocker), anexemplary embodiment of the Laragh Method provides that any patient on afull dose of a CEI or ARB with a PRA level less than 0.65 ng/ml/hr whoremains hypertensive should be switched a V drug. For patients who areon less than a full R drug dose and have PRA levels equal to or greaterthan 0.65, it is worthwhile to first test an increase in dose and/or addanother R drug before returning to the R side of Protocol I visit 4.

According to an exemplary embodiment of the Laragh Method, a patientwith a PRA equal to or greater than 0.65 ng/ml/hr who is unsuccessfullytreated with a full dose of any R drug (CEI, ARB or beta blocker) shouldthen have a V drug added as long as PRA is less than 6.5 ng/ml/hr. At orabove this level the patient should be treated with a second R drugbecause, although the three classes of R drugs all block therenin-angiotensin system, they have different sites of action and may beadditive for increasing inhibition of the renin system. Thus, at therecommended maximal therapeutic doses, neither CEIs nor ARBs arecomplete blockers of the renin system and a reactive rise in reninsecretion will sometimes overcome or attenuate the effectiveness ofthese agents in blocking the renin system. Moreover, beta blockers actto prevent the beta adrenergic drive to renin release, and may sometimesbe needed to amplify the anti-renin blockade achieved by a CEI or ARB orboth, each of which blocks the renin system at a different points.

Protocol IIC: For Unresponsive Hypertensive Patients Already Taking Oneor More R and V Drugs

According to an exemplary embodiment of the Laragh Method as indicatedin FIG. 5 and Table 7, a PRA test on the first visit is extremelyhelpful in this situation because it can reveal which mechanismpredominates. Thus, PRA values less than 0.65 clearly indicate asodium-volume excess is present and the patient should be treated ashaving a primary volume problem. The R drug should be stopped and asecond V drug added. Conversely, if the PRA is between 0.65 and 6.5, theanti-renin limb of treatment needs to be strengthened by the addition ofa second R drug. Above 6.5 ng/ml/hr, the V drug should be stoppedbecause it may be causing excessive reactive renin secretion. A second Rdrug can be added, if necessary.

Thus, to summarize, the strategy dictated by an exemplary embodiment ofthe Laragh Method is to strengthen the V limb for PRA less than 0.65 andstop the anti-renin drugs. When the PRA is between 6.5 and 0.65 an Rdrug should be added. However, for those patients with PRAs equal to orgreater than 6.5, the diuretic therapy should be stopped when the R limbis strengthened because such high renin values are usually associatedwith sodium-volume depletion and overly reactive renin secretion.

Suggested Changes in Therapy for Treated Patients on V Drugs Based onTheir Treatment PRA Levels

The same patients illustrated in FIG. 2 are again illustrated in FIG. 6but with suggested changes in treatment for those whose BP was notoptimally corrected. The solid lines (also shown in FIG. 2) and thedashed lines indicate the changes in PRA and BP induced by the first andsecond changes in treatment respectively.

Most patients with treated PRA levels less than 0.65 ng/ml/hr who aretaking a diuretic are likely to be successfully treated. If furtherreduction in BP is necessary a second V drug should be added.

Patients with PRA levels on a V drug between 0.65 and 6.5 ng/ml/hr mayhave both volume and vasoconstrictor components to their blood pressureand are likely to respond best to the addition of an R drug to the Vdrug.

Patients with PRA levels above 6.5 ng/ml/hr on V drug(s) may have had alarge reactive rise in PRA with the diuretic. If an R drug is added theyare likely to have an even greater rise in PRA levels which couldoverwhelm the effects of anti-renin system blockade. In them the V drugshould be stopped when the R drug is started. It is possible that suchpatients may eventually need a second R drug to completely control theirBP (dotted arrow). Renovascular hypertension is common in patients whoexhibit highly reactive renin levels.

Suggested Changes in Therapy for Treated Patients on R Drugs Based onTheir Treatment PRA Levels.

The same hypothetical patients illustrated in FIG. 3 are againillustrated in FIG. 7 but with suggested changes in treatment for thosewhose BP was not optimally corrected. The solid line indicates thechanges in PRA and BP caused by the first line of therapy (alsoillustrated in FIG. 3). The dashed lines indicate the changes in PRA andBP induced by the suggested change in treatment. The solid arrow headindicates the PRA (and BP) values that were used to determine furthertreatment.

Unsuccessfully treated patients with treatment PRA levels less than 0.65ng/ml/hr should be switched to a V drug. The low treatment PRA levelindicates that the patient was unresponsive to the R drug.

Unsuccessfully treated patients with treatment PRA levels between 0.65and 6.5 ng/ml/hr are likely to have both volume and vasoconstrictorcomponents to their blood pressure and are likely to respond best to thecombination of a V drug and an R drug.

Unsuccessfully treated patients with treatment PRA levels above 6.5ng/ml/hr may have had such a reactive rise in PRA with the R drug thatthey overwhelmed the anti-renin system blockade. In them the addition ofa V drug is not indicated because it could induce an even greater risein PRA. That is why the addition of a second R drug is indicated here.

The Laragh Method May Be Used to Evaluate and Treat Hypertensive Crises

The Laragh Method as applied to the evaluation and treatment ofhypertensive crises is superior to traditional strategies which focusentirely on blood pressure correction per se, perhaps on the assumptionthat this is the only relevant traditional target. Traditionalstrategies, however, are faulty because they fail to promptly identifythe causal mechanisms, while embodiments of the present invention allowprompt identification of causal mechanisms by immediately exploitingplasma renin testing and the blood pressure responses to specificpharmacologic probes to target causal mechanisms for more specificcorrective drug treatments.

Thus, in contrast to the Laragh Method, the traditional recommendedapproaches have relied heavily on I.V. nitroprusside or I.V. or oralcalcium channel blockers, either of which are seductive because theywill in fact at least partially reduce the high blood pressureimmediately. But at the same time, whenever there is no mechanisticdiagnosis, precious time is lost which could have been used to gainvital diagnostic information about the basic causal mechanisms involvingrenin-angiotensin and sodium-volume mechanisms. Moreover, in the case ofnitroprusside, serious risks from the labor-intensive procedure itselfand the associated higher costs, contribute negatively to the overallgoal of promptly determining causation. In short, sincerenin-angiotensin excess is the most common single cause of hypertensivecrises and of attendant severe vascular injury to heart, brain andkidney, the primary use of either nitroprusside or CCB's in fact oftenproves to be a sojourn of lost time during which hypotension may betransiently achieved but without establishing a definitive diagnosis.This leaves the physician unprepared to make the inevitable switch tothe correct drug class for treating the individual.

The spectrum of disorders associated with high blood pressure rangesfrom chronic mild uncomplicated hypertension to more severe andcomplicated forms of hypertensive syndromes, the most severe of whichare defined as either hypertensive emergencies or hypertensiveurgencies. While these more urgent and severe hypertensive states mayvary widely in their presentations, all involve an acceleration of thesame pathophysiologic abnormalities (the renin vasoconstrictor and thesodium-volume pressor mechanisms) that are involved in sustaining themilder or more slowly progressing forms of chronic hypertension.

The basic strategies and procedures embodied in the Laragh Method forachieving a mechanistic diagnosis and selecting the correct drugtreatment for the individual patient with a hypertensive crisis remainand are in principle like those applied to evaluation of milder forms ofhypertension. They are modified to achieve a mechanistic diagnosis andthe correct drug treatment in the most rapid, “fast-forward” modepossible. Thus, just as in milder hypertensive states the Laragh Methodprovides that the most effective approach to emergency or urgencysituations involves the assessment of the presence and degree of the twopathways that are sustaining the hypertensive condition, i.e., theplasma renin-angiotensin vasoconstrictor factor and the sodium-volumefactor.

The JNC (Joint National Commission on Detection, Evaluation, andTreatment of High Blood Pressure) classifies hypertensive crises aseither hypertensive “emergencies” or “urgencies”. Table 8 below listsseveral types of hypertensive crises categorized as either hypertensiveemergencies or hypertensive urgencies. Hypertensive emergencies arethose situations that require immediate blood pressure reduction, (notnecessarily to normal) in order to prevent or reduce the risk ofpotentially fatal target organ damage, from stroke, heart attack, heartfailure or kidney failure. Hypertensive urgencies are those situationsin which it is desirable to reduce BP within a few hours. Examplesinclude upper levels of stage 3 hypertension, hypertension with opticdisc edema, progressive target organ complications, and severeperioperative hypertension. TABLE 8 HYPERTENSIVE EMERGENCIES MalignantHypertension Other High Renin States:   Renal Ischemic Vascular Disease  Renal Vasculitis (scleroderma, periarteritis, lupus)   Renal Trauma  Renin-secreting tumors Adrenergic crises: pheochromocytoma, cocaineabuse, clonidine withdrawal Dissecting aortic aneurysm Hypertensiveencephalopathy Hypertension with stroke or impending stroke (TIA)Hypertension with pulmonary edema Hypertension with acute myocardialinfarction HYPERTENSIVE URGENCIES Hypertension with unstable anginaAccelerating or severe hypertension Perioperative hypertension Cocaineabuse Clonidine withdrawal Sodium-volume overload forms:   Acute renalfailure   Acute glomerulonephritis   Low urinary tract obstruction  Primary aldosteronism   Low renin essential hypertension withpseudopapilledema   Preeclampsia

Table 9 below lists most of the recognized hypertensive emergencies orurgencies and includes what is already known about renin-angiotensin orsodium-volume involvement in their causation or maintenance. It alsoincludes those conditions associated with excessive neuro-adrenalhormonal activity, related either to excessive central or adrenalmedullary-induced release of catecholamines, either noradrenalin,adrenalin or both. A large component of catecholamine pressor action caninvolve constriction of kidneys vessels leading to excess kidneyrenin-angiotensin release. TABLE 9 THE RENIN ANGIOTENSIN AND/OR SODIUM →VOLUME MEDIATION OF HYPERTENSIVE EMERGENCIES OR URGENCIES: A. DryVasoconstrictor-High Renin Forms (PRA ≧ 0.65) have signs of vascularinjury to heart, brain and kidneys. 1. Malignant Hypertension 2.Unilateral renovascular hypertension 3. High renin essentialhypertension 4. Renal Trauma or infarction 5. Renin-secreting tumors 6.Renal vasculitis (periarteritis, scleroderma, lupus) 7. AdrenergicCrises: pheochromocytoma, cocaine abuse, clonidine withdrawal 8. Cocaineabuse, clonidine withdrawal B. Wet-Sodium-Volume Mediated V Forms ofacute hypertension (Plasma Renin <0.65 to very low). 1. Acute renalfailure 2. Acute glomerulonephritis 3. Lower urinary tract obstruction4. Low renin essential hypertension 5. Primary hyperaldosteronism 6.Eclampsia (PRA falls from 6-10 range of normal pregnancy to 1-2ng/ml/hr) A. Mixed Renin-Sodium Volume Forms of Hypertension. The Degreeof ≧0.65 or <0.65 indicates a predominant renin or volume factor. 1.Bilateral renal artery stenosis the high blood pressure of theseconditions can 2. Coarctation of the aorta *The high blood pressure ofthese conditions can normally be volume dependent, but after sodiumdepletion it is sustained instead by plasma renin increase. D. Otherprobable* medium to high renin states: PRA ≧ 0.65 1. Hypertensiveencephalopathy 2. Hypertension with cerebral hemorrhage 3. Hypertensionwith (impending) stroke 4. Hypertension with pulmonary edema 5.Hypertension with acute myocardial infarction or with unstable angina 6.Dissecting aortic aneurysm 7. Perioperative hypertension (renininvolvement reactive to noradrenalin or adrenalin release).*These are hypertensive emergencies or urgencies for which no systematicinformation on plasma renin or sodium-volume states is yet available.Nonetheless, the Laragh Method's use of renin testing in conjunctionwith the blood pressure response to an R or V drug can still faithfullyreveal and target for treatment, the presence and/or degree of the reninor the sodium volume factor in sustaining the hypertension.

The Laragh Method provides a protocol for rapid evaluation and treatmentof hypertensive emergencies and urgencies and include, for example,those shown in Tables 8 and 9. In an exemplary embodiment, foraccelerating the processes to treat hypertensive crises, the LaraghMethod provides that the process begins by obtaining entry plasma reninactivity (PRA) and plasma catecholamine measurements along with testingblood for routine parameters. (See Table 10 below which sets forth anexemplary embodiment of this systematic approach.) This is followedimmediately thereafter by systematic testing of the blood pressureresponses at 30 to 60 minutes intervals, first after administering ananti-renin R drug, most preferably either I.V. enalaprilat or 50 mgcaptopril orally. As in the milder forms of hypertension, a largeresponse implicates plasma renin-angiotensin levels in causation whileno response suggests a sodium volume causation instead. TABLE 10Procedures For The Rapid Mechanistic Approach To Diagnosis And TreatmentOf Hypertensive Emergencies Or Urgencies: The Laragh Vasoconstriction(Renin Angiotensin-Sodium-Volume Analysis In Fast Forward 1. BaselineLaboratory Profile: CBC Plasma renin activity Plasma catecholamines:norepinephrine, epinephrine Electrolytes, urea, creatinine, uric acid,glucose ECG and Echo 2. Perform a rapid vasoconstriction(renin-angiotensin) (sodium-volume) analysis i.e.: Diagnosis exjuvantibus: the blood pressure response to the drug informs thediagnosis. Use I.V. or rapidly acting oral drugs in series, every 30-45minutes to determine BP response and inform the diagnosis. (1) Oralcaptopril or I.V. enalaprilat to identify the presence or absence of therenin factor. (2) I.V. Phentolamine plus esmolol or labetalol I.V. toquantify the neural factor and to rule out pheochromocytoma, cocaineabuse, or clonidine withdrawal. (3) I.V. furosemide to quantify thevolume factor. 3. Continue therapy with the effective agent(s) from theabove. Add or substitute non- specific vasodilators, BUT only if needed.Eg: I.V. nicardipine or verapamil, I.V. nitroprusside, nitroglycerine,hydralazine or diazoxide. 4. In bleeding states, e.g.: cerebral oraortic dissection, or in acute myocardial infarction use instead orfirst agents that reduce cardiac work and vascular wall stress (i.e.beta blockers). 5. As blood pressure falls with renin system blockadeconcurrent sodium volume repletion may be required. 6. The response orlack of response to the specific anti-renin (R) or anti-sodium (V) drugstaken together with follow-up plasma renin level also guide follow-updrug therapy.

The second pharmacologic testing step is designed to quickly rule in orout, whenever clinically appropriate, catecholamine (i.e., adrenalin ornoradrenalin) related hypertension from, for example, an adrenal tumor,(e.g., a pheochromocytoma), or from cocaine abuse or clonidine ormethyl-DOPA withdrawal any of which may induce catecholamine release. Infact, large plasma catecholamine surges, such as in a pheochromocytomaregularly elicit large renal renin release which then becomes a largefactor in causing this hypertension and a target for drug treatment. Thepharmacologic probes employed in this second step are most preferablyI.V. phentolamine with esmolol, to achieve combined alpha and betablockade or alternatively most preferably I.V. labetalol, a combinedalpha-beta blocker. A large blood pressure response implicates a neuralfactor, (e.g., a pheochromocytoma). If the above syndromes areclinically unlikely, pharmacologic testing for catecholamine involvementmay be deferred or omitted.

In a preferred embodiment, the next drug testing step evaluates theinvolvement of the sodium-volume factor by administering most preferablyI.V. furosemide and observing the blood pressure response to an inducednatriuresis over the ensuing several hours. (See Table 11 below.) Thistesting may be superimposed on the presence of continued anti-renin drugtherapy as indicated from step one especially if full dose R drugtherapy was only partially effective.

The response or lack of it to these pharmacologic probes, together withreturned results of the baseline plasma renin testing (usually availablewithin 24 hrs), enables assessment of the strength of the renin orsodium-volume factor and thereby informs the pathophysiologic basis forthe hypertension. Thus, the response to these drug types informs thediagnosis—diagnosis ex juvantibus. For partial responders, just as intreating office or clinic patients, follow-up renin testing can informthe correct second or third drug choice.

Thus, the Laragh Method allows the physician to make a tentativecategorical diagnosis of the underlying cause of the hypertensive crisisi.e., that the crisis is a result of the renin vasoconstrictor mechanismor the sodium-volume pressor mechanism. This tentative categoricaldiagnosis may be confirmed upon obtaining the PRA level results. TABLE11 PREFERRED PHARMACOLOGIC PROBES FOR IMPLEMENTING THE LARAGH METHOD FORRAPID VASOCONSTRICTION (I.E., RENIN-ANGIOTENSIN OR CATECHOLS) OR SODIUMINVOLVEMENT IN THE HYPERTENSIVE CRISIS The diagnostic approach(diagnosis ex juvantibus) Initial Dose Repeat Dose Onset of Drug 1.Anti-renin drug 1.25 mg I.V. bolus 2.5-10 mg 10-15 min    Enalaprilat9-30 min 2. Anti Sympathetic 20 mg I.V. bolus 20-80 mg   5 min   Labetalol 0.5-1.0 mg I.V. or 1-5 mg/min  1-2 min    or 1 mg/min   Phentolamine 0.1 ng/kg/min    plus    Esmolol    (Brevibloe) 3.Anti-sodium-volume 20-40 mg I.V. Bolus 80-200 mg   5 min    FurosemideInteractive Formats

In another embodiment, the Laragh Method may be used in an interactiveformat via, for example, an internet website or computer program. Suchan interactive format may be configured to accept patient informationsuch as patient history, clinical characteristics, blood pressure, andlab values. This embodiment of the Laragh Method can be configured to beable to deliver, almost instantly, diagnostic and treatmentrecommendations such as, for example, lab tests and drugs as describedabove. The interactive nature of such a website allows much of theinterviewing of patients and the input of clinical data to be carriedout by nurse practitioners or by other physician extenders, thus freeingthe physician from these time-consuming tasks and reducing the overallcost of treatment.

A further benefit of an interactive format embodiment of the LaraghMethod is the ability of this format to compile extensive patient data.Such compilations may be helpful in further diagnosis and treatmentrecommendations and maintenance.

As a specific example of an interactive format, a computer programqueries a user for patient information, such as blood pressure, previoustreatments and PRA lab values, among other information. The program maythen process this information and recommend a course of treatment basedon the Laragh Method as described herein. The computer program may thencompile the information entered, recommendations made and resultsobtained for one or more patients to provide useful data. The computerprogram may be made available in a computer readable format via, forexample, a disk, CD ROM or internet website.

Conclusion

Awareness and understanding of baseline ambulatory plasma renin levelsand various meaningful plasma renin response patterns toantihypertensive drugs helps the physician to find the simplest, mostrational, “best fit,” drug, or drug program, for each individualpatient. A goal is to use one drug instead of two, or two instead ofthree, for the long-term commitment that hypertension mandates. Thus,the Laragh Method directs that a little extra time be spent at thebeginning to work out the best drug fit program for each patient whichcan have big payoffs in efficacy, simplicity, cost, and compliance. Inthe long term, appropriate treatment ultimately may prevent serious,often fatal cardiovascular events, not to mention the physician andpatient gratifications inspired by their mutual involvement in arational treatment process.

The Laragh Method described herein enables the physician to determinethe simplest and best drug treatment program for each patient. Thissystem guides a decision tree for untreated new hypertensive patients aswell as for the hypertensive patient who is already on drugs, but whoseblood pressure is either not successfully treated, or whose medicationshould be changed, for clinical reasons, including unwanted sideeffects, or because the complexity of the regimen has led tonon-compliance. In addition, the Laragh Method may be applied to theevaluation and treatment of hypertensive crises. The Laragh Method hasbeen described herein in a number of specific examples. One skilled inthe art will understand that some of the specifics of the examples canbe varied to still apply the method and exploit its superior results.

1-13. (canceled)
 14. A method of treating a hypertensive patient havinga PRA greater than or equal to about 0.65 ng/ml/hr comprising: A.administering to the patient a low dose R drug; B. after step Ameasuring the patient's BP and if the patient's BP is not controlled,administering to the patient an increased dose of the R drug.
 15. Amethod for treating patients with hypertension who have a medium to highlevel plasma renin activity (PRA), comprising: A. prescribing a R drugat a low dose; B. increasing the dose of the R drug if a patient's bloodpressure (BP) is not adequately controlled after A; C. prescribing a Vdrug at a low dose in addition to the R drug if a patient's BP is notadequately controlled after B; D. increasing the dose of the V drug if apatient's BP is not adequately controlled after C, and measuring thePRA.
 16. A method for treating patients with hypertension who have a lowlevel plasma renin activity (PRA), comprising: A. prescribing a V drugat a low dose; B. increasing the dose of the V drug if a patient's bloodpressure (BP) is not adequately controlled after A.
 17. A method fortreating patients with hypertension who have a low level plasma reninactivity (PRA), comprising: A. prescribing a V drug at a low dose; B.increasing the dose of the V drug if a patient's blood pressure (BP) isnot adequately controlled after A; C. prescribing a R drug at a low dosein addition to the V drug if a patient's BP is not adequately controlledafter B; D. increasing the dose of the R drug if a patient's BP is notadequately controlled after C, and measuring the PRA.